Negative feedback autoregulation of the BRCA1 promoter is mediated by BRCA1.

DE SIERVI A; RUSTICI G; IDELMAN G; HAGGERTY CM; LONGO D; GARDNER K

USA

Congreso; 96th AACR Annual Meeting: American Association for Cancer Research.; 2006

Inherited mutations of BRCA1, a tumor suppressor, confer a high risk for breast cancer, ovarian cancer, and other type of human tumors. BRCA1 is involved in regulation of the DNA damage response, cell cycle progression, apoptosis, steroid hormone responses, and the maintenance of genomic integrity. The regulated expression of BRCA1 is likely to be one of the key factors controlling most of these processes. However, the mechanism through which BRCA1 is transcriptionally regulated is poorly understood. In this study we show that BRCA1 is a central component in the regulation of its own promoter via a novel negative feedback mechanism. By chromatin immunoprecipitation we find that BRCA1 is highly enriched at is own promoter in vivo. However, following treatment with genotoxic agents, BRCA1 is released and transcription at the BRCA1 promoter is increased. In synchronous populations of elutriated cells, BRCA1’s association with its promoter peaks in late G1 phase followed by a total release upon entrance into S phase and increased BRCA1 transcription. Depletion of endogenous levels of BRCA1 by RNAi causes marked up regulation of the transcriptional activity of co-transfected luciferase reporters containing the BRCA1 promoter. Accordingly, enforced expression of BRCA1 represses activity of co-transfected BRCA1 reporters and requires the end-terminal BRCA1 repeat region domain (BRCT) for full repressive activity. These findings describe an important new mechanism for the regulation of BRCA1. Moreover, this new mode of negative autoregulation implies that expression of BRCA1 is a self-activated process that requires its recruitment away from the BRCA1 promoter toward potential sites of repair and new DNA synthesis so that its critical role in maintaining genome integrity during DNA replication and against genotoxic stress can be fulfilled.